Fig. 3

Left panel—in the post prandial state, SGLT-2 is overactive and glucose and sodium are reabsorbed proximally; as a result, distal sodium delivery is reduced and reabsorption is stimulated by a relative activation of the renin–angiotensin–aldosterone system (RAAS) as well as by the physiological rise in insulin levels, which by themselves promote distal sodium reabsorption. The intensity of the grey filling indicates the intraluminal sodium concentration. When sodium concentration is low in the ascending limb of Henle, diuretics are likely to be less effective. Right panel—when SGLT-2 is inhibited, the intraluminal sodium concentration is increased throughout the nephron, less sodium is reabsorbed in the loop because of an increase in osmotic pressure, and less sodium is absorbed in the distal tubule because of lack of RAAS activation and lower insulin levels. When sodium concentration is higher in the ascending limb of Henle, diuretics are likely to be more effective. The histograms at the bottom reproduce sodium excretion rates in fasting and post-meal conditions in T2D subjects before (left) and after (right) SGLT-2 inhibition for 4 weeks